Complement C5a Induces Renal Injury in Diabetic Kidney Disease Via Disruption in Mitochondrial Metabolic Agility

Sih Min Tan, Mark Ziemann, Vicki Thallas-Bonke, Matthew Snelson, Vinod Kumar, Adrienne Laskowski, Tuong-Vi Nguyen, Kevin Huynh, Michele V. Clarke, Renata Libianto, Scott T Baker, Alison Skene, David Power, Richard J MacIsaac, Darren C Henstridge, Rick A Wetsel, Sam El-Osta, Peter Meikle, Scott Wilson, Josephine Maree Forbes & 4 others Mark Emmauel Cooper, Elif Ekinci, Trent M Woodruff, Melinda Coughlan

Research output: Contribution to journalArticleResearchpeer-review

Abstract

The sequelae of diabetes mellitus include microvascular complications such as diabetic kidney disease (DKD), which involves glucose-mediated renal injury that is associated with a disruption in mitochondrial metabolic agility, inflammation and fibrosis. We explored the role of the innate immune complement component C5a, a potent mediator of inflammation, in the pathogenesis of DKD in clinical and experimental diabetes. Marked systemic elevation in C5a activity was demonstrated in patients with diabetes which was not therapeutically targeted by conventional renoprotective agents. C5a and its receptor (C5aR1) were upregulated early in the disease process and prior to manifest kidney injury in several diverse rodent models of diabetes. Genetic deletion of C5aR1 in mice conferred protection against diabetes-induced renal injury. Transcriptomic profiling of kidney revealed diabetes-induced downregulation of pathways involved in mitochondrial fatty acid metabolism. Interrogation of the lipidomics signature revealed abnormal cardiolipin remodelling in the diabetic kidney, a cardinal sign of disrupted mitochondrial architecture and bioenergetics. In vivo delivery of an orally active inhibitor of C5aR1 (PMX53) reversed the phenotypic changes and normalized the renal mitochondrial fatty acid profile, cardiolipin remodelling and citric acid cycle intermediates. In vitro exposure of human renal proximal tubular epithelial cells to C5a led to altered mitochondrial respiratory function and reactive oxygen species generation. These studies provide evidence for a pivotal role of the C5a/C5aR1 axis in propagating renal injury in the development of DKD via disruption of mitochondrial agility, establishing a new immunometabolic signalling pathway in DKD.
Original languageEnglish
JournalDiabetes
DOIs
Publication statusAccepted/In press - 17 Oct 2019

Cite this

Tan, Sih Min ; Ziemann, Mark ; Thallas-Bonke, Vicki ; Snelson, Matthew ; Kumar, Vinod ; Laskowski, Adrienne ; Nguyen, Tuong-Vi ; Huynh, Kevin ; Clarke, Michele V. ; Libianto, Renata ; Baker, Scott T ; Skene, Alison ; Power, David ; MacIsaac, Richard J ; Henstridge, Darren C ; Wetsel, Rick A ; El-Osta, Sam ; Meikle, Peter ; Wilson, Scott ; Forbes, Josephine Maree ; Cooper, Mark Emmauel ; Ekinci, Elif ; Woodruff, Trent M ; Coughlan, Melinda. / Complement C5a Induces Renal Injury in Diabetic Kidney Disease Via Disruption in Mitochondrial Metabolic Agility. In: Diabetes. 2019.
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title = "Complement C5a Induces Renal Injury in Diabetic Kidney Disease Via Disruption in Mitochondrial Metabolic Agility",
abstract = "The sequelae of diabetes mellitus include microvascular complications such as diabetic kidney disease (DKD), which involves glucose-mediated renal injury that is associated with a disruption in mitochondrial metabolic agility, inflammation and fibrosis. We explored the role of the innate immune complement component C5a, a potent mediator of inflammation, in the pathogenesis of DKD in clinical and experimental diabetes. Marked systemic elevation in C5a activity was demonstrated in patients with diabetes which was not therapeutically targeted by conventional renoprotective agents. C5a and its receptor (C5aR1) were upregulated early in the disease process and prior to manifest kidney injury in several diverse rodent models of diabetes. Genetic deletion of C5aR1 in mice conferred protection against diabetes-induced renal injury. Transcriptomic profiling of kidney revealed diabetes-induced downregulation of pathways involved in mitochondrial fatty acid metabolism. Interrogation of the lipidomics signature revealed abnormal cardiolipin remodelling in the diabetic kidney, a cardinal sign of disrupted mitochondrial architecture and bioenergetics. In vivo delivery of an orally active inhibitor of C5aR1 (PMX53) reversed the phenotypic changes and normalized the renal mitochondrial fatty acid profile, cardiolipin remodelling and citric acid cycle intermediates. In vitro exposure of human renal proximal tubular epithelial cells to C5a led to altered mitochondrial respiratory function and reactive oxygen species generation. These studies provide evidence for a pivotal role of the C5a/C5aR1 axis in propagating renal injury in the development of DKD via disruption of mitochondrial agility, establishing a new immunometabolic signalling pathway in DKD.",
author = "Tan, {Sih Min} and Mark Ziemann and Vicki Thallas-Bonke and Matthew Snelson and Vinod Kumar and Adrienne Laskowski and Tuong-Vi Nguyen and Kevin Huynh and Clarke, {Michele V.} and Renata Libianto and Baker, {Scott T} and Alison Skene and David Power and MacIsaac, {Richard J} and Henstridge, {Darren C} and Wetsel, {Rick A} and Sam El-Osta and Peter Meikle and Scott Wilson and Forbes, {Josephine Maree} and Cooper, {Mark Emmauel} and Elif Ekinci and Woodruff, {Trent M} and Melinda Coughlan",
year = "2019",
month = "10",
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journal = "Diabetes",
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Complement C5a Induces Renal Injury in Diabetic Kidney Disease Via Disruption in Mitochondrial Metabolic Agility. / Tan, Sih Min; Ziemann, Mark; Thallas-Bonke, Vicki; Snelson, Matthew; Kumar, Vinod ; Laskowski, Adrienne; Nguyen, Tuong-Vi; Huynh, Kevin; Clarke, Michele V.; Libianto, Renata; Baker, Scott T; Skene, Alison; Power, David; MacIsaac, Richard J; Henstridge, Darren C; Wetsel, Rick A ; El-Osta, Sam; Meikle, Peter; Wilson, Scott; Forbes, Josephine Maree; Cooper, Mark Emmauel; Ekinci, Elif; Woodruff, Trent M; Coughlan, Melinda.

In: Diabetes, 17.10.2019.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Complement C5a Induces Renal Injury in Diabetic Kidney Disease Via Disruption in Mitochondrial Metabolic Agility

AU - Tan, Sih Min

AU - Ziemann, Mark

AU - Thallas-Bonke, Vicki

AU - Snelson, Matthew

AU - Kumar, Vinod

AU - Laskowski, Adrienne

AU - Nguyen, Tuong-Vi

AU - Huynh, Kevin

AU - Clarke, Michele V.

AU - Libianto, Renata

AU - Baker, Scott T

AU - Skene, Alison

AU - Power, David

AU - MacIsaac, Richard J

AU - Henstridge, Darren C

AU - Wetsel, Rick A

AU - El-Osta, Sam

AU - Meikle, Peter

AU - Wilson, Scott

AU - Forbes, Josephine Maree

AU - Cooper, Mark Emmauel

AU - Ekinci, Elif

AU - Woodruff, Trent M

AU - Coughlan, Melinda

PY - 2019/10/17

Y1 - 2019/10/17

N2 - The sequelae of diabetes mellitus include microvascular complications such as diabetic kidney disease (DKD), which involves glucose-mediated renal injury that is associated with a disruption in mitochondrial metabolic agility, inflammation and fibrosis. We explored the role of the innate immune complement component C5a, a potent mediator of inflammation, in the pathogenesis of DKD in clinical and experimental diabetes. Marked systemic elevation in C5a activity was demonstrated in patients with diabetes which was not therapeutically targeted by conventional renoprotective agents. C5a and its receptor (C5aR1) were upregulated early in the disease process and prior to manifest kidney injury in several diverse rodent models of diabetes. Genetic deletion of C5aR1 in mice conferred protection against diabetes-induced renal injury. Transcriptomic profiling of kidney revealed diabetes-induced downregulation of pathways involved in mitochondrial fatty acid metabolism. Interrogation of the lipidomics signature revealed abnormal cardiolipin remodelling in the diabetic kidney, a cardinal sign of disrupted mitochondrial architecture and bioenergetics. In vivo delivery of an orally active inhibitor of C5aR1 (PMX53) reversed the phenotypic changes and normalized the renal mitochondrial fatty acid profile, cardiolipin remodelling and citric acid cycle intermediates. In vitro exposure of human renal proximal tubular epithelial cells to C5a led to altered mitochondrial respiratory function and reactive oxygen species generation. These studies provide evidence for a pivotal role of the C5a/C5aR1 axis in propagating renal injury in the development of DKD via disruption of mitochondrial agility, establishing a new immunometabolic signalling pathway in DKD.

AB - The sequelae of diabetes mellitus include microvascular complications such as diabetic kidney disease (DKD), which involves glucose-mediated renal injury that is associated with a disruption in mitochondrial metabolic agility, inflammation and fibrosis. We explored the role of the innate immune complement component C5a, a potent mediator of inflammation, in the pathogenesis of DKD in clinical and experimental diabetes. Marked systemic elevation in C5a activity was demonstrated in patients with diabetes which was not therapeutically targeted by conventional renoprotective agents. C5a and its receptor (C5aR1) were upregulated early in the disease process and prior to manifest kidney injury in several diverse rodent models of diabetes. Genetic deletion of C5aR1 in mice conferred protection against diabetes-induced renal injury. Transcriptomic profiling of kidney revealed diabetes-induced downregulation of pathways involved in mitochondrial fatty acid metabolism. Interrogation of the lipidomics signature revealed abnormal cardiolipin remodelling in the diabetic kidney, a cardinal sign of disrupted mitochondrial architecture and bioenergetics. In vivo delivery of an orally active inhibitor of C5aR1 (PMX53) reversed the phenotypic changes and normalized the renal mitochondrial fatty acid profile, cardiolipin remodelling and citric acid cycle intermediates. In vitro exposure of human renal proximal tubular epithelial cells to C5a led to altered mitochondrial respiratory function and reactive oxygen species generation. These studies provide evidence for a pivotal role of the C5a/C5aR1 axis in propagating renal injury in the development of DKD via disruption of mitochondrial agility, establishing a new immunometabolic signalling pathway in DKD.

U2 - 10.2337/db19-0043

DO - 10.2337/db19-0043

M3 - Article

JO - Diabetes

JF - Diabetes

SN - 0012-1797

ER -